Because lipopolysaccharide (LPS;endotoxin), a component of the outer cell membrane of Gram-negative bacteria, is released into the circulation of patients with septic shock and is a pathogenic toxin, LPS-reactive monoclonal antibodies are being investigated for treatment of septic shock. The known effects of LPS-reactive monoclonal antibodies vary with antibody binding site on the LPS molecule (core, lipid A, or O-side chain regions). Although O-side chain reactive monoclonal antibodies have consistently demonstrated protection in previous experiments, the protection associated with core or lipid A reactive monoclonal antibodies has varied among antibodies and experiments. In a clinical trial, patients with Gram- negative sepsis given a murine core-reactive antibody (5) had increased resolution of multiple organ failure. (18) In a multicenter clinical trial of the HA-1A antibody, humans with sepsis gram-negative bacteremia that had been given HA-1A had reduced mortality, although there was no effect of the antibody overall. Experimental results suggest that protection provided by O-side chain reactive monoclonal antibodies is derived from antibacterial activity. In contrast, the protection provided by core or lipid A reactive monoclonal antibodies is less defined, though it may be derived from anti- endotoxic activity and not antibacterial activity. To examine the effects and mechanisms of protection for different core/lipid A and O-side chain reactive monoclonal antibodies and their interaction with antibiotic treatment, we plan experiments in a canine model that simulates the serial (28) hemodynamic changes of human septic shock. The effect of antibody binding specificity on survival, serial circulating endotoxin levels, quantitative blood cultures, hemodynamics and other clinical variables will be examined in animals with Gram-negative septic shock.